Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation

Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Wnt as it does not signal by stabilizing β-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Wnt pathway by promoting the degradation of β-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and β-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote β-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.

Download Full-text

Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro

PLoS ONE ◽

10.1371/journal.pone.0101894 ◽

2014 ◽

Vol 9 (7) ◽

pp. e101894 ◽

Cited By ~ 26

Author(s):

Fan Hu ◽

Li Xu ◽

Zhi-Hua Liu ◽

Meng-Meng Ge ◽

Di-Yun Ruan ◽

...

Keyword(s):

Lead Exposure ◽

Wnt Pathway ◽

Canonical Wnt Pathway ◽

Canonical Wnt

Download Full-text

Efficiency of Cell Therapy to GC-Induced ONFH: BMSCs with Dkk-1 Interference Is Not Superior to Unmodified BMSCs

Stem Cells International ◽

10.1155/2018/1340252 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Wei Zhun ◽

Li Donghai ◽

Yang Zhouyuan ◽

Zhao Haiyan ◽

Kang Pengde

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Cell Therapy ◽

Wnt Pathway ◽

Allograft Bone ◽

Canonical Wnt Pathway ◽

Canonical Wnt ◽

Dickkopf 1

Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a hip disorder, and it threatens patients who require megadose of steroid therapies. Nowadays, no valid therapies can reverse the development of GC-induced ONFH once it occurs. Stem cell therapy to GC-induced ONFH would be a promising choice. Although the pathogenesis of GC-induced ONFH is not yet fully clear, Dickkopf-1 (Dkk-1) upregulated by excessive GC use, which hinders the canonical Wnt pathway, could be an explanation. Thus, the aim of the present work lies in investigating the efficiency of the allograft bone marrow stem cells (BMSCs) with Dkk-1 interference in preventing the progression of the GC-induced ONFH. Lentivirus-meditated Dkk-1 RNAi was introduced into BMSCs which was exposed to dexamethasone (10−6 mol/L) in vitro. This interference blocked Dkk-1 overexpression by GC and afterwards prompted the transduction of Wnt/β-catenin in which the Runx2 and PPARγ were upregulated and downregulated, respectively. Thus, the osteogenesis was promoted while adipogenesis was inhibited. In vivo, GC-induced ONFH rats were treated by allotransplantation of BMSCs with Dkk-1 interference, and the progression of the disease was prevented. However, the effects were not significantly superior to treatment with nongenetically modified or normal BMSCs.

Download Full-text

Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway

Development ◽

10.1242/dev.127.10.2227 ◽

2000 ◽

Vol 127 (10) ◽

pp. 2227-2238 ◽

Cited By ~ 43

Author(s):

M. Tada ◽

J.C. Smith

Keyword(s):

Wnt Pathway ◽

Target Genes ◽

Dominant Negative ◽

Beta Catenin ◽

Transcription Activator ◽

Amphibian Embryo ◽

Morphogenetic Movements ◽

Canonical Wnt Pathway ◽

Canonical Wnt

Gastrulation in the amphibian embryo is driven by cells of the mesoderm. One of the genes that confers mesodermal identity in Xenopus is Brachyury (Xbra), which is required for normal gastrulation movements and ultimately for posterior mesoderm and notochord differentiation in the development of all vertebrates. Xbra is a transcription activator, and interference with transcription activation leads to an inhibition of morphogenetic movements during gastrulation. To understand this process, we have screened for downstream target genes of Brachyury (Tada, M., Casey, E., Fairclough, L. and Smith, J. C. (1998) Development 125, 3997–4006). This approach has now allowed us to isolate Xwnt11, whose expression pattern is almost identical to that of Xbra at gastrula and early neurula stages. Activation of Xwnt11 is induced in an immediate-early fashion by Xbra and its expression in vivo is abolished by a dominant-interfering form of Xbra, Xbra-En(R). Overexpression of a dominant-negative form of Xwnt11, like overexpression of Xbra-En(R), inhibits convergent extension movements. This inhibition can be rescued by Dsh, a component of the Wnt signalling pathway and also by a truncated form of Dsh which cannot signal through the canonical Wnt pathway involving GSK-3 and (beta)-catenin. Together, our results suggest that the regulation of morphogenetic movements by Xwnt11 occurs through a pathway similar to that involved in planar polarity signalling in Drosophila.

Download Full-text

Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3β: autoregulation of GSK-3β in vivo

Biochemical Journal ◽

10.1042/bj20140207 ◽

2015 ◽

Vol 466 (2) ◽

pp. 415-430 ◽

Cited By ~ 38

Author(s):

Cheril Tapia-Rojas ◽

Andreas Schüller ◽

Carolina B. Lindsay ◽

Roxana C. Ureta ◽

Cristóbal Mejías-Reyes ◽

...

Keyword(s):

Ligand Binding ◽

Wnt Pathway ◽

Target Genes ◽

Competitive Inhibition ◽

Wnt Signalling ◽

Signalling Pathway ◽

Canonical Wnt Pathway ◽

Gsk 3Β ◽

Canonical Wnt

Andrographolide activates the canonical Wnt pathway and induces the transcription of Wnt target genes through a mechanism independent of Wnt ligand binding to its receptor, by direct substrate-competitive inhibition of GSK-3.

Download Full-text